Major depressive disorder (MDD) will affect 1 in 6 Americans during their lifetime but only 30% of MDD patients achieve remission. Underlying this treatment gap is a lack of comprehensive knowledge of depression etiology. A large body of evidence in both human patients and animal models points to a pivotal role for the immune system in depression. Depressed humans and animal models exhibit elevated levels of inflammatory cytokines in peripheral blood and central nervous system tissue. Our preliminary evidence in both humans and mice indicates that heightened peripheral inflammation is not simply a consequence of stress, but is rather a pre-existing state that increases susceptibility to stress and subsequent development of depression-like behavior. We have further shown that pre-existing differences in stress responsive Interleukin-6 (IL-6) release from bone marrow-derived leukocytes predict and functionally drive behavioral response to repeated social stress in mice. The molecular basis for these pre-existing differences is largely unknown. One possibility is the let-7 family of microRNAs (miRs), which has been shown to directly repress IL-6 mRNA. In this proposal, I will investigate the role of let-7 miRs in regulating IL-6 levels and subsequent stress susceptibility in mice. I will characterize baseline and stress-induced expression of let-7 miRs and IL-6 mRNA in leukocytes of mice susceptible and resilient to repeated stress. I will genetically reprogram leukocytes by overexpressing let-7 miRs to reduce circulating IL-6 and promote resilience to stress. These studies will inform our understanding of depression and reveal novel target mechanisms for therapeutic development.